Findings of the Independent Academic Prostate Studies in CLARITY-BPA - PowerPoint PPT Presentation

Findings of the Independent Academic Prostate Studies in CLARITY-BPA Gail S. Prins, PhD CLARITY-BPA InvesDgator University of Illinois at Chicago

Early-life BPA Exposure Increases Prostate Cancer Susceptibility BPA (10 µ g/kg BW) No PCa Birth Puberty Adult á PCa Estrogen incidence ↑ E/T in aging men Ho, et al, Cancer Research , 2006; Prins, et al, Repro Toxicology , 2011; Prins et al, Environ Health Perspec8ves , 2017

CLARITY-BPA: Prostate Independent Study: Prins laboratory Dorsolateral Prostate SUMMARY • Repeated previous findings: • Increased prostate cancer risk • Greatest effect at lowest BPA dose i.e. 2.5 µg/kg BPA

Low-dose BPA increased E 2 -induced adenocarcinoma multiplicity Tumor Numbers Dorso-Lateral Prostate Ducts: • Increased multiplicity of ductal adenocarcinoma in 2.5 µ g BPA (P<0.01 vs Vehicle). Trending for higher doses; borderline significance in parametric analysis.

How might early-life BPA exposure affect prostate cancer susceptibility later in life, long after BPA is cleared from the body? Prostate Epithelial Cell Hierarchy unipotent basal progenitor Basal Bipotent Progenitor Stem Cell Luminal unipotent luminal progenitor niche Neuroendocrine ? BPA transit self-renewal differentiation amplification

CLARITY-BPA: Examined the stem and progenitor cells from BPA-exposed rat prostates Animal Tx at FDA-NCTR Workflow at UIC Prostasphere (PS) Assay and Passage

Chronic exposure to low-dose BPA increased prostate stem cell numbers and progenitor cell proliferation Passage 3 – Total PS # Passage 3 – PS > 80 µM 700 700 PS number (>40um)/10,000 cells * PS number (>80um)/10,000 cells 600 600 * 500 500 400 400 300 300 † † 200 200 100 100 0 0 Veh 0.5 2.5 25 250 Veh 0.5 2.5 25 250 EE2 BPA EE2 BPA ( µ g/kg BW/day) ( µ g/kg BW/day) Representative of Representative of progenitor cell proliferation stem cell number Symmetric Symmetric Self-renewal CommiWed division

Chronic low-dose EE and BPA (25 and 250 µ g/kg) exposures alter progenitor cell lineage commitment Basal Progenitor Pattern Luminal Progenitor Pattern 1.6 10 CK8 CK5 mRNA Levels (Fold Change) mRNA Levels (Fold Change) 1.4 Tbx 3 ‡ Sox 2 Trop 2 Hox b13 8 1.2 Sox 9 ‡ 1.0 6 0.8 † ‡ * * 4 0.6 ‡ * * † 0.4 ‡ 2 ‡ ‡ 0.2 0.0 0 Vehicle EE 2.5 25 250 Vehicle EE 2.5 25 250 BPA ( m g/kg) BPA ( m g/kg) See a shift towards increased basal progenitor lineage at the expense of decreased luminal progenitor lineage

CLARITY-BPA Prostate Study: Summary Model Ø How might the stem cell changes influence PCa susceptibility? • Cancer risk is highly correlated to # normal stem cell divisions in most tissues, including prostate. (Tomasetti & Vogelstein, Science , 2015, 2017) • Tumor initiating cells for human PCa are largely localized to basal cell population. (Goldstein et al, Science, 2010) Ø Propose : Chronic in vivo low-dose BPA exposures ↑ prostate stem cell numbers and altered lineage commitment underpinning an increased carcinogenic risk with aging Prins et al, Environ Health Perspectives Nov;126(11):117001, 2018